Background: Methotrexate has been widely used as an effective systemic therapy for psoriasis. Retrospective data showed efficacy rate of 70-80% but recent RCTs using PASI 75 as primary endpoint showed wide variations in efficacy. Different dosing regimens for methotrexate may explain this variation. Objectives: To compare the efficacy and tolerability of two different dosing regimes of oral methotrexate in patients with moderate to severe plaque psoriasis. Methods: A prospective comparative study was conducted from October 2009 to June 2010. Patients with moderate-to-severe plaque psoriasis were randomized to receive either a ‘step-up dose’ regime (starting dose 7.5mg) or a ‘step-down dose’ regime (starting dose 20mg) of oral methotrexate for 16 weeks. The primary efficacy endpoint was PASI 75. Tolerability and safety were assessed. Results: Forty patients received oral methotrexate with equal numbers in each arm. After 16-week, 55% (11) of patients in ‘step-up dose’ group and 65% (13) of patients in ‘step-down dose’ group achieved PASI 75 (p > 0.05). Significantly higher number of patients in ‘step-down dose’ group achieved PASI 75 at week 4 and week 8 (p < 0.05) compared to ‘step-up dose’ group. One patients from ‘step-down dose’ group discontinued study prematurely due to adverse effect but no significant difference in rate of adverse events was noted. Conclusion: There was no significant difference in efficacy between both regimes at the end of 16 weeks but significant efficacy was observed in patients on ‘step-down dose’ regime as early as week 4. The side effect profile and tolerability were similar.